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MALIGNANT PLEURAL MESOTHELIOMA Giovanni Luca Ceresoli Humanitas Gavazzeni Bergamo Oncologia Medica POST IASLC Milano MALIGNANT PLEURAL MESOTHELIOMA Giovanni Luca Ceresoli Humanitas Gavazzeni Bergamo Oncologia Medica POST IASLC Milano 8 NOV 2013

Unmet needs in MPM 1. Role of surgery and radiotherapy (IMRT) 2. How to Unmet needs in MPM 1. Role of surgery and radiotherapy (IMRT) 2. How to improve results of first-line treatments 3. Role of second-line treatments 4. Response radiological assessment 5. Better understanding of the biology of the disease Oncologia Medica POST IASLC Milano 8 NOV 2013

MPM in WCLC 2013 1 Abstract presented during Plenary Session 1 Oral Abstract Session MPM in WCLC 2013 1 Abstract presented during Plenary Session 1 Oral Abstract Session 2 Mini Oral Abstract Sessions 3 Poster Sessions 2 Mini-Simposia 5 MTE Sessions SURGERY & MULTIMODALITY TREATMENTS SECOND-LINE TREATMENTS RESPONSE EVALUATION BIOLOGY Oncologia Medica POST IASLC Milano 8 NOV 2013

Role of surgery (P/D vs EPP) Non surgical group imbalanced: older than surgical pts, Role of surgery (P/D vs EPP) Non surgical group imbalanced: older than surgical pts, less epithelioid, less treated with chemotherapy P/D not homogeneous (different centers, 30 -yr span) 1227 evaluable pts, from 1982 to 2012 in 6 Institutions Oncologia Medica Bille et al. , WCLC 2013 POST IASLC Milano 8 NOV 2013

Role of surgery (P/D vs EPP) (age <70 yrs, epitheliod type, chemotherapy) 313 pts Role of surgery (P/D vs EPP) (age <70 yrs, epitheliod type, chemotherapy) 313 pts with favorable prognostic factors (25%) Oncologia Medica Bille et al. , WCLC 2013 POST IASLC Milano 8 NOV 2013

P/D in MPM: different techniques IMIG/IASLC consensus, JTO 2011; Cao et al. , WCLC P/D in MPM: different techniques IMIG/IASLC consensus, JTO 2011; Cao et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

175 patients Primary endpoint: 1 -yr OS; secondary endpoints: Qo. L, control of pleural 175 patients Primary endpoint: 1 -yr OS; secondary endpoints: Qo. L, control of pleural effusion Rintoul et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

The meso. VATs trial: survival Rintoul et al. , WCLC 2013 Oncologia Medica POST The meso. VATs trial: survival Rintoul et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

The meso. VATs trial: Qo. L & pleural effusion control 1. No difference in The meso. VATs trial: Qo. L & pleural effusion control 1. No difference in overall survival; 2. P/D has a modest advantage in Qo. L and effusion control; 3. P/D: more toxicities & lenght of stay in hospital, more expensive. Rintoul et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Hemithoracic pleural IMRT after P/D 20 pts have completed RT, 1 is on treatment. Hemithoracic pleural IMRT after P/D 20 pts have completed RT, 1 is on treatment. 5 pts with grade 2 RP, 1 grade 3; early intervention with steroids effective in controlling RP. Wu et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

PI 3 K/m. TOR INHIBITORS IN SECOND-LINE SETTING IN MPM GDC 0980, 30 mg PI 3 K/m. TOR INHIBITORS IN SECOND-LINE SETTING IN MPM GDC 0980, 30 mg orally daily Phase I + MPM expanded cohort at P 2 RD Overall 33 pts; 4 PR, RR 12% PI 3 K mutations and p. TEN loss uncommon Oncologia Medica Dolly et al. , WCLC 2013 POST IASLC Milano 8 NOV 2013

Oncologia Medica POST IASLC Milano 8 NOV 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Oncologia Medica POST IASLC Milano 8 NOV 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013 Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013 Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013 Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

SS 1 P plus PC in MPM Hassan et al. , WCLC 2013 Oncologia SS 1 P plus PC in MPM Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

SS 1 P plus PC in MPM Hassan et al. , WCLC 2013 Oncologia SS 1 P plus PC in MPM Hassan et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

VINORELBINE and BRCA 1 in MPM Sensitivity to vinorelbine correlates with BRCA 1 expression VINORELBINE and BRCA 1 in MPM Sensitivity to vinorelbine correlates with BRCA 1 expression in 6 mesothelioma cell lines. 38. 9 % 61. 1 % Busacca et al. , J Pathol 2012 9 Oncologia Medica POST IASLC Milano 8 NOV 2013

VINORELBINE and BRCA 1 in MPM Randomised phase II trial of oral vinorelbine as VINORELBINE and BRCA 1 in MPM Randomised phase II trial of oral vinorelbine as second-line therapy for patients with MPM expressing BRCA 1 – VIM trial Relapsed MPM Weekly oral VINORELBINE + ASC R ASC (active symptom control) 2: 1 BRCA 1 expression IHC will be evaluated as a stratification factor. Primary endpoint: overall survival. 114 participants required (76 VNR, 38 ASC) Fennell et al. , Poster Session 2 Mesothelioma, P 2. 14 -013 9 Oncologia Medica POST IASLC Milano 8 NOV 2013

Tremelimumab: an anti-CTLA-4 m. Ab T-cell costimulatory receptors • Tremelimumab (CP 675, 206) Pfizer/Med. Tremelimumab: an anti-CTLA-4 m. Ab T-cell costimulatory receptors • Tremelimumab (CP 675, 206) Pfizer/Med. Immune Ig. G 2 isotype antibody half-life time: 22 days T-cell potentiation T cell CTLA-4 TCR MHC B 7 APC Oncologia Medica POST IASLC Milano 8 NOV 2013 CTLA-4 m. Ab

Immunotherapy in MPM: tremelimumab Calabrò et al. , Lancet Oncol 2013 Oncologia Medica POST Immunotherapy in MPM: tremelimumab Calabrò et al. , Lancet Oncol 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Phase II Multicenter, International, Randomized Trial of Tremelimumab in Patients With Unresectable Mesothelioma (Trial Phase II Multicenter, International, Randomized Trial of Tremelimumab in Patients With Unresectable Mesothelioma (Trial D 4880 C 00003 Sponsored by Med. Immune) Relapsed/Refractory Malignant Mesothelioma (2 nd/3 rd line) Total recruitment = 180 patients (OS events) 2: 1 Treme 10 mg/kg Q 4 Wk x 6 doses Placebo Q 4 Wk x 6 doses Primary endpoint: OS Treme 10 mg/kg Q 12 Wk (Non Dosing visits: V 9, 11, 13) Placebo Q 12 Wk (Non Dosing visits: V 9, 11, 13) NCT 01843374 ü Randomized TREMELIMUMAB: PLACEBO 2: 1 (120/60) ü Stratification Factors § § § European Organization for Research and Treatment of Cancer (EORTC) status (lowrisk vs high-risk) Line of therapy (second vs third) Anatomical site (pleural vs peritoneal) Kindler et al. , Poster Session 2 Mesothelioma, P 2. 14 -015 Oncologia Medica POST IASLC Milano 8 NOV 2013 23

Focal adhesion kinases (FAK) inhibitors in MPM ü Pemetrexed and cisplatin increase cancer stem Focal adhesion kinases (FAK) inhibitors in MPM ü Pemetrexed and cisplatin increase cancer stem cells (CSCs). ü FAK inhibitors decrease CSCs in mesothelioma models. ü NF 2 tumor suppressor gene is inactivated in 40 -50% of MPM pts, resulting in lack of expression of functional Merlin protein. ü Mesothelioma cells that lack NF 2/Merlin are especially sensitive to FAK inhibitors. Poulikakos et al. , Oncogene 2006 Oncologia Medica POST IASLC Milano 8 NOV 2013

Focal adhesion kinases (FAK) inhibitors in MPM: VS-6063 (or Carbo/Cis) 1: 1 Primary Endpoint: Focal adhesion kinases (FAK) inhibitors in MPM: VS-6063 (or Carbo/Cis) 1: 1 Primary Endpoint: PFS Approx. 370 pts included Keegan et al. , Poster Session 2 Mesothelioma, P 2. 14 -014 Oncologia Medica POST IASLC Milano 8 NOV 2013

Volumetric CT tumor response in MPM Armato et al. , WCLC 2013 Oncologia Medica Volumetric CT tumor response in MPM Armato et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Volumetric CT tumor response in MPM Semi-automated method to determine MPM volume from CT Volumetric CT tumor response in MPM Semi-automated method to determine MPM volume from CT scans retrospectively collected from 70 patients undergoing standard of care chemotherapy. Armato et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Volumetric CT tumor response in MPM 41 consecutive radical P/D CONCLUSIONS 1. OS and Volumetric CT tumor response in MPM 41 consecutive radical P/D CONCLUSIONS 1. OS and PFS were correlated with tumor volume (TV). 2. All radiographic techniques underestimated actual TV. 3. Estimates closer to actual TV as they became less automated and more manual. Friedberg et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Gene sequencing CDKN 2 A, NF 2 and BAP 1 are the most frequently Gene sequencing CDKN 2 A, NF 2 and BAP 1 are the most frequently mutated genes in MPM Oncologia Medica POST IASLC Milano 8 NOV 2013

BAP-1 SYNDROME MALIGNANT MESOTHELIOMA UVEAL MELANOMA MELANOCYTIC BAP-1 MUTATED ATYPICAL INTRADERMAL TUMOURS CUTANEOUS MELANOMA BAP-1 SYNDROME MALIGNANT MESOTHELIOMA UVEAL MELANOMA MELANOCYTIC BAP-1 MUTATED ATYPICAL INTRADERMAL TUMOURS CUTANEOUS MELANOMA Carbone et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Tissue microarray from 170 epithelioid MPM, MSKCC Ujiiee et al. , WCLC 2013 Oncologia Tissue microarray from 170 epithelioid MPM, MSKCC Ujiiee et al. , WCLC 2013 Oncologia Medica POST IASLC Milano 8 NOV 2013

Conclusions 1. The debate on surgery in MPM continues: expanding role of P/D, meso. Conclusions 1. The debate on surgery in MPM continues: expanding role of P/D, meso. VATs. 2. IMRT after P/D or no surgery. 3. Medical treatment: SS 1 P plus PC promising; new options/studies: BRCA 1/vinorelbine, tremelimumab, FAK-inhibitors. 4. Volumetric CT response evaluation: pitfalls and challanges. 5. Biology: gene sequencing, BAP 1 syndrome. Role of the immune system. Oncologia Medica POST IASLC Milano 8 NOV 2013